The gut microbiome: a contributing mechanism to the anti-seizure effect of topiramate
Epilepsy is one of the most common neurological disorders worldwide. This neurological disorder is characterized by spontaneous recurrent seizures and impacts about 65 million people globally. As there is no cure for epilepsy, the treatment goal for patients is seizure management, and ultimately seizure freedom. The first line of defense in seizure management is anti-epileptic drugs, which aim to restore the excitatory and inhibitory balance in the brain. Unfortunately, about 30% of people with epilepsy are drug resistant, a number which has remained unchanged despite the increasing amount of anti-epileptic drugs. This leads patients to seek alternative treatments, which include surgery, vagus nerve stimulation, or diet alterations such as the ketogenic diet. Due to the invasiveness of surgeries, difficulty to maintain specialty diets, or lack of effectiveness of these treatments in some patients, additional therapies are needed.
The gut-brain axis is a bidirectional communication network connecting the central and enteric nervous systems. Part of this network includes communication via the gut microbiota. The gut microbiota consists of all the microorganisms living in the gut, including bacteria, viruses, and fungi. It is involved in aiding nutrient absorption, promoting the maturation of immune cells and functions, and protection against pathogens. There is growing interest in the role of the gut microbiome in human health and disease. Studies have shown that patients with epilepsy have altered gut microbiomes compared to healthy controls, and that gut microbiome alteration can impact seizure frequencies. These exciting findings have ignited research on the potential therapeutic role of the gut microbiome in epilepsy. Although studies have explored the impact of alterations in the gut microbiome on seizure activity, they have not studied how anti-epileptic drugs may contribute to this relationship. Thus, this dissertation explores the role of the commonly prescribed anti-epileptic drug topiramate on the gut microbiome. Fecal samples of mice treated with topiramate were analyzed using 16S ribosomal RNA gene sequencing. Analysis revealed that topiramate ingestion increased the probiotic bacteria Lactobacillus johnsonii in the gut microbiome. In addition, cotreatment of topiramate and Lactobacillus johnsonii reduced seizure susceptibility in a pentylenetetrazol-kindling seizure model. Moreover, cotreatment increased the butyrate producing family Lachnospiraceae and subsequently increased the neuroprotective SCFA, butyrate in the gut microbiome. Importantly, cotreatment also resulted in an increased GABA/glutamate ratio in the cortex of mice that underwent pentylenetetrazol-kindling. These results are the first to demonstrate that the anti-seizure effect of topiramate may be facilitated by the modulation of the gut microbiota via increasing butyrate and altering the GABA/glutamate ratio in the cortex. Lastly, this work highlights the potential for probiotics as an adjuvant therapy in seizure management.